Pentafluorosulfanyl-substituted biaryl derivatives as MATE-type transporter inhibitors targeting drug-resistant bacteria.

Multidrug and toxin extrusion (MATE) inhibitors improve the antimicrobial susceptibility of drug-resistant bacteria by preventing the efflux of administered antibiotics. In this study, we optimized the chemical structure of a previously identified bacterial-selective MATE inhibitor 1 (EC50 > 30 µM) to improve its activity further. Compound 1 was divided into three fragments (aromatic part, linker part, and guanidine part), and each part was individually optimized. Compound 31 (EC50 = 1.8 µM), a novel pentafluorosulfanyl-containing molecule synthesized following optimized parts, showed antimicrobial activity against MATE-expressing strains at concentrations lower than conventional inhibitor 1 when co-administrated with norfloxacin. Furthermore, 31 was not cytotoxic at effective concentrations. This suggests that compound 31 can be a promising candidate for combating bacterial infections, particularly those resistant to conventional antibiotics by MATE expression.

Age-Related Changes in the Utilization of Visual Information for Collision Prediction: A Study Using an Affordance-Based Model.

The ability to predict collisions with moving objects deteriorates with aging. We followed the affordance-based model to identify optical variables that older adults had difficulty using for collision prediction. We reproduced a modified version of the interception task used in Steinmetz (Steinmetz, Layton, Powell, & Fajen, 2020, "Affordance-based versus current - future accounts of choosing whether to pursue or abandon the chase of a moving target," Journal of Vision, 20(3), 8) in a virtual reality (VR) environment and newly introduced perturbation for each of three optical variables (vertical and horizontal expansions of a moving object and the bearing angle produced between participants and a moving object). We expected that perturbation would negatively affect the performance only for those who rely on the optical variable to perform the interception task effectively. We tested 18 older and 15 younger adults and showed that older participants were not negatively affected by the perturbation for the vertical and horizontal expansion of a moving object, while they showed decreased performance when the perturbation was introduced with a bearing angle. These findings suggest that predicting collisions with moving objects deteriorates with aging because the perception of object expansion is impaired with aging.

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks.

In recent years, hydrofluorocarbon compounds such as chlorofluorocarbons, hydrochlorofluorocarbons, and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) have been used as fluorine-containing building blocks to construct functional fluorine-containing compounds, e. g., polymers, liquid crystals, and medicines. Hydrofluorocarbons promote the formation of reactive fluoroalkyl or fluoroalkenyl species via anionic or radical processes, and these species can act as nucleophiles or electrophiles depending on the reaction conditions. Progress in fluorine chemistry using hydrofluorocarbons in the last 30 years is described in this review and diverse reactions are discussed, including the fluoroalkyl/alkenyl products and proposed mechanisms involved.

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone.

A rhodium-catalyzed intramolecular reductive aldol-type cyclization is described to give ß-hydroxylactones with high diastereoselectivities. The stereoselectivity of this cyclization is highly solvent dependent and can give syn- or anti-ß-hydroxylactones with high diastereoselectivity. This methodology was also applied to the synthesis of a chiral necic acid lactone which is a structural component of the pyrrolizidine alkaloid monocrotaline.

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane).

A series of aryl fluoroalkenyl ethers that contain chlorine and bromine as well as fluorine atoms were prepared in moderate to good yields via the reactions of phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) in the presence of KOH. This simple reaction enabled the construction of highly halogenated compounds with the potential for further functionalization. The reaction involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH.

Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections.

Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.

Discovery of benzyloxyphenyl- and phenethylphenyl-imidazole derivatives as a new class of ante-drug type boosters.

Although cytochrome P450 3A4 (CYP3A4) inhibitors are used as boosters to increase drug absorption, the inhibition of CYP3A4 activity may affect the metabolism of other co-administered drugs. Therefore, we screened for and developed a new class of boosters to improve the oral availability of drugs. We identified benzyloxyphenyl imidazole and phenethylphenyl imidazole derivatives as new types of CYP3A4 inhibitors. Among the compounds synthesized, an ester 5c was found to inhibit CYP activity and the compound 5c was gradually converted to an inactive metabolite 5d under physiological conditions, indicating that the ester 5c may represent a novel ante-drug type booster.

Improved Walking Through an Aperture in a Virtual Environment Transfers to a Real Environment: Introduction of Enriched Feedback and Gradual Increase in Task Difficulty.

Virtual reality (VR) could be used to set up a training protocol to improve one's collision-avoidance behavior. In our previous study, we developed a VR system for training older individuals to walk through an aperture in a manner that is both safe (i.e., no collision) and efficient (i.e., no exaggerated behavior to ensure collision avoidance). In the present study, we made several modifications to the VR system in terms of enriched feedback (vibratory stimulation for virtual collisions and the addition of positive feedback for successful trials) and gradual increase in task difficulty during training to strengthen the skill transfer. Nineteen older adults (74.4 ± 5.3 years of age) and 21 younger adults (25.1 ± 5.0 years of age) participated. They were randomly assigned to one of two training groups: the intervention group (older: n = 10; younger: n = 10) or the control group (older: n = 11; younger: n = 9). The experiment consisted of pre- and post-training tests in a real environment and training in a VR environment. During training, participants held a horizontal bar while stepping in place as if a VR image on the screen were moving in response to their stepping. Participants in the intervention group tried to pass a narrow aperture without collision while attempting to minimize their body rotation to avoid collision as much as possible. The criterion upon which the collision-avoidance behavior was regarded as successful became incrementally more demanding as participants successfully met the previous criterion. Participants in the control group passed through a very wide aperture, so that collision-avoidance behavior was unnecessary. A comparison between pre- and post-training test performances showed that, for both older and younger adults in the intervention group, the spatial margins became significantly smaller, while the success rate remained unchanged. For those in the control group, neither the spatial margin nor the success rate was improved. These results suggest that the three modifications made for the VR system contributed to improvement of the system and helped participants transfer the behavior learned from the VR environment to real walking.

LCP: Simple Representation of Docking Poses for Machine Learning: A Case Study on Xanthine Oxidase Inhibitors.

In this paper, we propose a simple descriptor called the ligand coordinate profile (LCP) for describing docking poses. The LCP descriptor is generated from the coordinates of the polar hydrogen and heavy atoms of the docked ligand. We hypothesize that the prediction of binding poses can be enhanced through the combination of machine learning methods with the LCP descriptor. Two docking programs were used to predict ligand docking against xanthine oxidase. Four machine learning methods-k-nearest neighbors, random forest, support vector machine, and LightGBM-were used to determine whether machine learning-based models could be used to accurately identify the correct binding poses. Regardless of the machine learning method employed, the LCP descriptor demonstrated improved performance compared to the existing descriptor. The results of the leave-one-pdb-out approach revealed that the influence of the pose descriptor was also significant, as demonstrated through cross-validation. When evaluated using top-N metrics, the machine learning models were generally more effective than the docking programs. In addition, the LCP-based models outperformed those based on the existing descriptor. The results obtained in this study suggest that our proposed binding pose descriptor is effective for improving the docking accuracy of xanthine oxidase inhibitors.

Importance of the Azole Moiety of Cimetidine Derivatives for the Inhibition of Human Multidrug and Toxin Extrusion Transporter 1 (hMATE1).

Herein, we describe the design and synthesis of cimetidine analogs, as well as their inhibitory activity toward the human multidrug and toxin extrusion transporter 1 (hMATE1), which is related to nephrotoxicity of drugs. Cimetidine is the histamine H2-receptor antagonist, but also inhibits hMATE1, which is known to cause renal impairment. We designed and synthesized cimetidine analogs to evaluate hMATE1 inhibitory activity to reveal whether the analogs could reduce the inhibition of hMATE1. The results showed that all analogs with an unsubstituted guanidino group exhibited hMATE1 inhibitory activity. On the other hand, there was a clear difference in the hMATE1 inhibitory activity for the other compounds. That is, compounds with a methylimidazole ring exhibited hMATE1 inhibition, while compounds with a phenyl ring did not. The results suggest that the ability to form hydrogen bonds at the azole moiety is strongly involved in the hMATE1 inhibition.

Identification and Synthesis of DDI-6, a Quinolinol Analog Capable of Activating Both Caenorhabditis elegans and Mouse Spermatozoa.

Sperm activation is an essential process by which the male gametes become capable of fertilization. Because the process in Caenorhabditis elegans is readily reproducible in vitro, this organism serves as an excellent model to investigate it. C. elegans sperm activation in vivo occurs during spermiogenesis. Membranous organelles (MOs) contained within spermatids fuse with the plasma membrane, resulting in extracellular release of their contents and relocation of some proteins indispensable for fertilization from the MO membrane onto the sperm surface. Intriguingly, these cytological alternations are exhibited similarly in mouse spermatozoa during the acrosome reaction, which also represents a form of sperm activation, prompting us to hypothesize that C. elegans and mice share a common mechanism for sperm activation. To explore this, we first screened a chemical library to identify compounds that activate C. elegans spermatozoa. Because a quinolinol analog named DDI-6 seemed to be a candidate sperm activator, we synthesized it to use for further analyses. This involved direct dechlorination and hydrogenolysis of commercially available 5-chloro-8-quinolinol, both of which are key steps to yield 1,2,3,4-tetrahydro-8-quinolinol, and we subsequently introduced the sulfonamide group to the compound. When C. elegans spermatids were stimulated with solvent alone or the newly synthesized DDI-6, approx. 3% and approx. 28% of spermatids became MO-fused spermatozoa, respectively. Moreover, DDI-6 triggered the acrosome reaction in approx. 20% of mouse spermatozoa, while approx. 12% became acrosome-reacted after mock stimulation. Thus, DDI-6 serves as a moderately effective activator for both C. elegans and mouse spermatozoa.

[Effectiveness of a program promoting community activities for the prevention of frailty using a community assessment].

AIM: We developed a program to promote community activities for preventing frailty using the Community-as-Partner model. We aimed to clarify whether or not participants' extent of practice relating to frailty prevention activities increased after the classroom, as well as the effectiveness of the program for preventing frailty. METHODS: The participants were recruited from among pre-frailty and frailty individuals in a cohort study of community-dwelling older adults. Thirty-two participants completed the classroom intervention. Thereafter, every three months, through a telephone survey, the participants were asked about the extent of practice regarding their frailty prevention activities. The Kihon Checklist and Japanese version of the Cardiovascular Health Study (J-CHS) frailty index were surveyed as outcome measures during the cohort study conducted six months before the classroom (baseline [BL]) as well as approximately one year after this intervention (follow-up [FL]). The changes in the outcome measures between the BL and FL in the intervention group were compared to those in the control group matched by the propensity score. RESULTS: The frailty prevention activities saw a maximum increase around six to nine months after the classroom. The J-CHS frailty index showed a group × time-of-survey significant interaction (F = 6.531, p=0.012) and significantly decreased from 1.3 at BL to 0.8 at FL in the intervention group (p=0.009). CONCLUSIONS: The practice of activities relating to frailty prevention increased after the classroom, and the participants also showed improvements in their physical frailty. The present program seems likely to be effective preventing frailty.

Effect of Learning Dataset for Identification of Active Molecules: A Case Study of Integrin αIIbß3 Inhibitors.

Efficient in silico approaches are needed to identify strong integrin αIIbß3 inhibitors through a small number of measurements. To address the challenge, we investigated the effect of learning dataset on the classification performance of machine learning models focusing on weak and inactive compounds. The structure and activity information of the compounds were obtained from ChEMBL, and pCHEMBL values were used to classify them as active, inactive, or weak. Datasets with various imbalance levels from active:inactive=1 : 1 to 1 : 1000 were used for the machine learning. The prediction scores of the weak samples were found to lie between the predictive values of active and inactive compounds. In addition, another dataset that consists of 149 actives and 6.9 million inactives was screened; the results indicated that the number of positive predictions decreased for models trained with a higher number of inactives. Although there is a trade-off between false positives and false negatives, for determination of compounds with strong activity using a reduced number of measurements, it is better to use a large number of inactives for learning and identifying compounds that score higher than the weak samples.

Synthesis of aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers through the base-mediated reaction between phenols and halothane.

An efficient and convenient method for the synthesis of structurally unique and highly functionalized aryl 2-bromo-2-chloro-1,1-difluoroethyl ethers has been developed. This approach exhibits a broad reaction scope, a simple operation and without the need of any expensive transition-metal catalyst, highly toxic or corrosive reagents. Notably, we demonstrate the potential utility of halothane for the synthesis of aryl gem-difluoroalkyl ethers containing the bromochloromethyl group.

Transient Respiratory-motion Artifact and Scan Timing during the Arterial Phase of Gadoxetate Disodium-enhanced MR Imaging: The Benefit of Shortened Acquisition and Multiple Arterial Phase Acquisition.

PURPOSE: To investigate whether shortened acquisition or multiple arterial phase acquisition improves image quality of the arterial phase compared with conventional protocol. METHODS: This retrospective study was approved by the relevant Institutional Review Board. A total of 615 consecutive patients who underwent gadoxetate disodium-enhanced MRI including one of the following three sequences in three different periods were included: (i) conventional liver acquisition with volume acceleration (LAVA) (between October 2014 and January 2015, n = 149), (ii) Turbo-LAVA (between March and August 2016, n = 216), and (iii) differential sub-sampling with Cartesian ordering (DISCO) (between January and September 2015, n = 250). We monitored the respiratory bellows waveform during breath holding for each patient and recorded breath-hold fidelity of the patients. Two radiologists independently evaluated the degree of respiratory artifact and scan timing on the arterial phase and compared them between the three protocols (i.e., conventional LAVA, Turbo-LAVA, and DISCO), with conventional LAVA as control. RESULTS: The ratio of patients with breath-hold failure was not significantly different among the three protocols (P = 0.6340 and 0.1085). Respiratory artifact was significantly lower in DISCO than in conventional LAVA (P = 0.0424), while there was no significant difference between Turbo-LAVA and conventional LAVA (P = 0.2593). The ratio of adequate scan timing and diagnosable image defined as no or mild artifact and adequate scan timing were higher in DISCO than in conventional LAVA (P = 0.0025 and 0.0019), while there was no significant difference between Turbo-LAVA and conventional LAVA (P = 0.0780 and 0.0657). CONCLUSION: Compared with conventional protocol, multiple arterial phase acquisition (DISCO) obtained a higher number of diagnosable images by reducing respiratory motion artifact and optimizing the scan timing of arterial phase.

[An implementation study of a program supporting frailty-prevention community activities using the "Community-as-Partner" model].

Objectives　We hypothesized that the motivation for improving physical function could be increased by increasing the awareness of social role expectations among frail community-dwelling older adults through an intervention based on the Community-as-Partner (CAP) model. We also developed a program for supporting community activities to prevent frailty, utilizing the CAP model. Program feasibility was assessed by implementing it under the local government's frailty prevention service.Methods　The CAP-based program consisted of a "learning period," a "regional issue extraction period," and a "practice period," scheduled once a week for four months. Public health nurses and/or physical therapists assisted with the program. The intervention was conducted with a cohort study of community-dwelling older adults. About 160 participants identified as frail and pre-frail on the Kihon Checklist were recruited. Program feasibility was assessed through participation rate, number of pre-frail and frail individuals, and drop-out rate; scores of a pre-post intervention questionnaire assessing the understanding of frailty and regional resources; and behavioral change stage on frailty prevention.Results　A total of 42 participants were recruited (participation rate=26.3%; 25 were pre-frail and 17 were frail). The drop-out rate was 23.8% (n=10). The scores on four out of five items and six out of eleven items on the understanding of frailty and regional resources, respectively, improved significantly after the intervention. Regarding the behavioral change stage, 26 participants (81.2%) maintained or improved.Conclusion　The participation rate was approximately 30%, similar to conventional programs with direct professional intervention. Conversely, a higher drop-out rate compared to conventional programs suggested the importance of explaining the workshop in the program introduction and publicizing the workshop. The results indicated that the program improved the understanding of frailty and regional resources, and led to behavioral change for frailty prevention.

Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles.

Fluorescent molecules based on a fluorinated isoxazole scaffold were synthesized and investigated for their photochemical properties. The introduction of a fluorine substituent into 3,5-diarylisoxazoles led to an increase of fluorescence intensity and exhibited a redshift in the emission intensity. α-Fluorinated boron ketoiminates (F-BKIs) were also synthesized via a ring-opening reaction of 4-fluoroisoxazoles and exhibited highly fluorescent luminescence and aggregation-induced emission (AIE), showing promise as a new fluorophore.

Copper-Catalyzed Oxidative Trifluoromethylation of Terminal Alkenes Using AgCF3.

A mild and convenient reaction for oxidative trifluoromethylation of terminal alkenes was developed using in situ generated AgCF3 in the presence of a copper catalyst. The reaction proceeded under an air atmosphere to afford trifluoromethylated allylic compounds in moderate to good yield. This reaction, with no need for highly hygroscopic or corrosive reagents, features not only a simple operation but also various functional group tolerances.

Effect of Structural Descriptors on the Design of Cyclin Dependent Kinase Inhibitors Using Similarity-based Molecular Evolution.

In this study, we evaluated the effect of structural descriptors on the in silico design of bioactive compounds. The authors have proposed a molecular design technique for designing new bioactive compounds. In this approach, known fragments are combined to generate new structures, which are evolved to increase the similarity to a known active compound. We generated the structure of CDK2 inhibitors using four descriptors (three binary fingerprints and a numerical vector) to evaluate the effect of descriptors on the molecular design. Subsequently, the physicochemical properties of the generated compounds were compared and evaluated from a similarity viewpoint. As a result, it was clarified that better structures can be generated by using descriptors consisting of numerical vectors rather than binary fingerprints. Moreover, the compound generated using the numerical vector or a long-bit fingerprint resulted in favorable docking scores. Although binary fingerprints such as MACCS are widely used in this field, this result shows that it is important to use numeric vectors, or at least to use long-bit fingerprints, to design drug-like CDK2 inhibitors by the similarity-based structure generation.

Influence of Age on Global and Regional Brain Stiffness in Young and Middle-Aged Adults.

BACKGROUND: An understanding of potential age-related changes in brain stiffness and its regional variation is important for further clinical application of MR elastography. PURPOSE: To investigate the effect of age on global and regional brain stiffness in young and middle-aged adults. STUDY TYPE: Prospective. SUBJECTS: Fifty subjects with normal brains and aged in their 20s, 30s, 40s, 50s, or 60s (five men, five women per decade). FIELD STRENGTH/SEQUENCE: 3.0T MRI and elastography with a vibration frequency of 60 Hz. ASSESSMENT: Stiffness was measured in nine brain regions (cerebrum, temporal lobes, sensorimotor areas, frontotemporal composite region, deep gray matter and white matter (deep GM/WM), parietal lobes, occipital lobes, frontal lobes, and cerebellum) using an atlas-based region-of-interest approach. The influence of age on regional brain stiffness was evaluated. STATISTICAL TESTS: Multiple linear regression analysis, followed by Dunnett's multiple comparisons test, using subjects in their 20s as controls. RESULTS: Following adjustment for sex, multiple linear regression revealed a significant negative correlation between age and stiffness of the cerebrum (P < 0.0001), temporal lobes (P < 0.0001), sensorimotor areas (P < 0.0001), frontotemporal composite region (P < 0.0001), deep GM/WM (P = 0.0028), parietal lobes (P < 0.0001), occipital lobes (P = 0.0055), and frontal lobes (P < 0.0001). Dunnett's multiple comparison test showed that the stiffness of the sensorimotor areas, frontotemporal composite region, and frontal lobes was significantly decreased in subjects in their 40s (P < 0.0367), 50s (P < 0.0001), and 60s (P < 0.0001), while that of the cerebrum, temporal lobes, and parietal lobes was significantly decreased only in subjects in their 50s (P < 0.0012) and 60s (P < 0.0031) when compared with the controls. DATA CONCLUSION: There is an age-related decrease in brain stiffness that varies across the different regions. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:727-733.